This project aims to create a hand-held active instrument for manual micromanipulation that compensates physiological hand tremor and other unintended motion by generating an equal but opposite deflection of its own tip, enabling positioning accuracy of approximately 10 l_m. This hand-held instrument, which we have named "Micron," will thus be able to replace automated micromanipulators for many tasks. The instrument will implement filtering algorithms for both tremor and non-tremulous movement errors. The device is designed both for microinjection and micromanipulation in the cell biology laboratory, and for clinical microsurgery (especially vitreoretinal), and is therefore relevant to both basic science and clinical applications. An exploratory research (R21) phase, now nearing completion, has resulted in a fully operational prototype and a demonstration of effective error canceling to the level of roughly 28 _m p-p (12 _m rms). The exploratory phase has also revealed that the stringent accuracy requirement of this application places unusual demands on the research, particularly in sensing of the instrument tip motion. If the goal of 10 l_m p-p noise is to be reached, the types of kinematic approximations that are typical in robotic applications cannot be used. The research proposed herein will involve advanced design developments, kinematic computations, and development of zero-phase filtering concepts to enable sufficient sensing accuracy. The tip micromanipulator design will also be modified to incorporate a new minimal-hysteres is actuation scheme, as well as closed-loop control using strain gauge sensing. Initial tests will be conducted using a motorized testbed. The instrument will then be field tested in realistic settings. Experimental trials will be conducted with human users in the cell biology laboratory. Preclinical microsurgical evaluation will be conducted in the surgical practice suite. This will include tests in vitro with cadaveric porcine eyes, as well as animal experiments in vivo.